Proofreading Is Too Noisy For Effective Ligand Discrimination

Kinetic proofreading (KPR) has been used as a paradigmatic explanation for the high specificity of important biological processes including ligand discrimination by cellular receptors. Kinetic proofreading enhances the difference in the mean receptor occupancy between different ligands, thus potentially enabling better discrimination. On the other hand, proofreading also attenuates the signal, increasing the relative magnitude of noise in the downstream signal. This can interfere with reliable ligand discrimination. To understand the effect of noise on ligand discrimination beyond the comparison of the mean signals, we formulate the task of ligand discrimination as a problem of statistical estimation of the molecular affinity of ligands. Our analysis reveals that proofreading typically worsens ligand resolution which decreases with the number of proofreading steps under most commonly considered conditions. This contrasts with the usual notion that kinetic proofreading universally improves ligand discrimination with additional proofreading steps. Our results are consistent across a variety of different proofreading schemes, suggesting that they are inherent to the KPR mechanism itself rather than any particular model of molecular noise. Based on our results, we suggest alternative roles for kinetic proofreading schemes such as multiplexing and combinatorial encoding in multi-ligand/multi-output pathways. ### Competing Interest Statement The authors have declared no competing interest.